HCM occurs in 1:500 in the general population and is characterized by severe thickening of left ventricular (LV)walls. It often causes disabling symptoms and is the most common cause of sudden death in otherwise healthy subjects such as athletes. Genetic Etiology: HCM may be caused by mutations in one of 8 genes that encode sarcomeric genes.However, the molecular defects identified to date probably account for about half of HCM cases. We have identified novel mutations in the following sarcomeric genes: alpha-tropomyosin (TPM), myosin- binding protein-C, cardiac actin, and beta-myosin heavy chain (MYH7). Several families in which HCM is not caused by known genes are being evaluated by linkage studies. DNA samples from about 500 affected patients are also being screened for mutations in genes that are candidates for causing HCM. Genotype-Phenotype Correlations Although family members with the identical mutation often have significantly different clinical presentations, the phenotype in HCM is determined importantly by the genetic defect. Gene-Specific Cardiac Morphology: LV hypertrophy in mid-cavity HCM occurs most prominently at the level of the papillary muscles and may be associated with an apical aneurysm. This rare cardiac phenotype occurs more commonly in patients with mutations of the essential and regulatory light chains of myosin. In some patients with this mutation, the hypertrophied papillary muscles obliterate the LV apex and give the appearance of apical HCM. Therefore, some forms of apical HCM may represent earlier stages of mid-cavity HCM. Mutation-Specific Disease Penetrance and Natural History: The type of mutation also determines disease penetrance (per cent of subjects with mutation who develop HCM) and prognosis. Most MHY7 mutations are associated with almost complete disease penetrance and a high incidence of sudden death. In contrast, some MYH7 mutations are associated with low disease penetrance and a benign prognosis. The cardiac phenotype often skips one or more generations in these families. HCM caused by a novel V95A TPM mutation is associated with mild hypertrophy but a high incidence of sudden death. Mutation- Specific Etiologies of Sudden Death: The mechanism of sudden death may also be related to the type of mutation. For example, presyncope, syncope, and sudden death have been strongly associated with exercise- induced myocardial ischemia in patients with HCM caused by the R403Q MYH7 mutation. The symptoms of impaired consciousness may be treated successfully with verapamil and beta-blocker therapy. In some families the genetic defect is associated with other distinct cardiac abnormalities, such as pre-excitation syndrome, long QT interval, or heart block. Mutation-Specific Functional Abnormalities: The MYH7 mutations occur in different functional domains of the head or the head-rod junction of the molecule. It is therefore likely that the mutations have different effects on the function of the molecular motor. The motility test is an elegant way of studying functional abnormalities caused by mutations at a molecular level. In this assay, myosin is bound to a coverslip using an antibody to the tail. The myosin heads are free to translocate fluorescently-labeled actin. Mutations would be expected to affect the velocity with which the myosin translocates actin. Indeed, the velocities of fluorescently- labeled actin are depressed by certain mutations, but are increased by others. The novel V95A TPM mutation associated with a malignant form of HCM causes increased thin filament calcium affinity and altered myosin cycling. Further evidence that sarcomeric mutations have specific effects on the molecular motor is provided by the demonstration that single cardiac myosin molecules from patients with HCM caused by R403Q and L908V MYH7 mutations exhibit abnormal mechanical performance in the laser trap assay. Mutation-Specific Skeletal Muscle Mechanical Abnormalities: Demonstration that some mutations are expressed in skeletal muscle has also permitted study of differences in several mechanical properties of single skeletal muscle fibers from patients with HCM caused by distinct mutations such as fiber stiffness (proportional to the number of strongly attached cross-bridges), force:stiffness ratio (an indication of the force generated per cross- bridge in normal fibers), and maximum unloaded velocity of shortening (used to quantify the physiologic rate of cross-bridge cycling during fiber activation). For example, skeletal fibers with the R403Q MYH7 mutation demonstrate a lower force:stiffness ratio and depressed velocity of shortening. Fibers from HCM patients with the E741G MYH7 mutation demonstrate decreased maximum velocity of shortening and decreased isometric force generation. The E741G and R403Q mutation- containing fibers both displayed abnormal force-velocity relationships and reduced power output. In contrast, fibers from patients in whom HCM was caused by the G256E MYH7 mutation had contractile properties indistinguishable from those of normal controls. Therefore, the nature and extent of functional impairments in skeletal fibers containing different MYH7 mutations may correlate with the severity and penetrance of HCM. Mutation-Specific Skeletal Myopathy: Certain sarcomeric genes, such as MYH7, myosin light chains, and TPM are also expressed in skeletal muscle and may be associated with specific skeletal myopathy. Microscopic examination of biopsies of soleus muscle from patients with HCM caused by MYH7 mutations has identified a skeletal myopathy similar to central core disease, characterized by predominance of type I slow fibers and absence of mitochondria in the center of many type I fibers. HCM caused by essential and regulatory light chains of myosin is also associated with specific skeletal myopathy, notably, a ragged red fiber pattern characteristic of mitochondrial myopathies.Dilated Cardiomyopathy DCM represents an important economic burden and need for cardiac transplantation. There is family history of DCM in about a third of cases. We have studied several families with familial DCM. Mutations in functional domains of the cardiac actin gene that affect force generation may cause HCM, but those that interfere with force transmission may cause DCM.